1. Field of the Invention
This invention relates to novel muramyldipeptide derivatives and to process for preparing the same. More particularly, this invention relates to muramyldipeptide derivatives represented by the general formula (1). ##STR2## wherein Y represents a mycoloyl group or a synthetic higher acyl group having total carbon number of C30-C90 and having at least a branched chain of long alkyl group on the .alpha.-position thereof, and Q represents an -L-alanyl-D-isoglutamine group,
A -glycyl-D-isoglutamine group or PA1 An -L-seryl-D-isoglutamine group. PA1 Q represents an -L-alanyl-D-isoglutamine group, PA1 Z can be a benzyl group which may have a halogen atom, a nitro group or a lower-alkoxy group, PA1 X can be a protective group for carboxyl group such as tertiary butyl group or a diphenylmethyl group, PA1 Y can be a mycoloyl group and a synthetic higher acyl group having total carbon number of C30-C90 and having at least a long branched chain of alkyl group on the .alpha.-position thereof, PA1 Q can be an -L-alanyl-D-isoglutamine group, PA1 Q' can be a protective L-alanyl-D-isoglutamine group, a protective glycyl-D-isoglutamine group or a protective L-seryl-D-isoglutamine group. PA1 (a) The compounds of this invention have a simple and definite structure in comparison with bacterial cell wall or its cell wall skeleton, therefore can be synthetically prepared in highly pure uniform component as possible in chemicals. PA1 (b) As the object compound of this invention can be suspended with phosphate buffered saline, the suspension may be administered intravenously without any severe side effect. While, an intradermal or intramuscular injection of oil-in-water suspension of cell wall skeleton of bacteria, from which such uniform suspension can not be prepared, may give side effect such as severe tissue reaction inavoidably. PA1 (c) The object compounds of this invention have less possibility of having antigenic properties, than those of conventional immunoadjuvant substances as recognized in Freund's complete adjuvant. To demonstrate superiority, the pharmacological properties of several representative compounds of this invention were compared with those of muramyldipeptide and stearoyl muramyldipeptide which are structually similar to the object compound of this invention. PA1 6-O-mycomycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine obtained in Example 1 = myco-L-Ala-D-isoGln. PA1 6-O-nocardomycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine obtained in Example 2 = nocardo-L-Ala-D-isoGln PA1 6-O-corynomycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine obtained in Example 3 = coryno-L-Ala-D-isoGln PA1 6-O-mycomycoloyl-N-acetylmuramyl-glycyl-D-isoglutamine obtained in Example 4 = myco-Gly-D-isoGln PA1 6-O-mycomycoloyl-N-acetylmuramyl-L-ser-D-isoglutamine obtained in Example 5 = myco-L-Ser-D-isoGln
This invention also relates to salts of such derivatives and to the method of preparing such derivatives and their salts. The compounds have potent immunoadjuvant activity and antitumor activity on syngenic mouse tumor systems such as MH134 hepatoma in C.sub.3 H/He, and melanoma B16 in C57BL/6J and then being applicable to agents for the immunotherapy of cancer for humans and animals.
2. Description of the prior art
Up to now, it has been reported that bacterial cell wall or the mucopeptide-containing wax D and a peptideglycolipid component of bacterial cell wall have immunoadjuvant activities. As the results of extensive studies on these known substances it has been also revealed that the minimal unit responsible for exhibition of adjuvant activity is N-acetylmuramyl-L-alanyl-D-isoglutamine (hereinafter referred to as "muramyldipeptide"). The muramyldipeptide showed immunoadjuvant activity such as stimulation of increased serum antibody levels and also induction of delayed-type hypersensitivity to an ovalmin protein antigen. It has been further reported by the inventors that 6-O-stearoyl-muramyldipeptide has immunological properties almost similar to those of muramyldipeptide. These two synthetic adjuvants, however, showed no adjuvant activity in the generation of cell-mediated cytotoxic effector cells on the spleen of C57BL/6J mice by the immunization with allogeneic antigen, mastocytoma P815-X2 cell in vivo. Cell-mediated cytotoxic activity closely relates to cellular immune responses and antitumor activity. It has also been demonstrated that these two compounds showed no antitumor activity on syngeneic mouse tumor systems such as MH134 hepatoma in C.sub.3 H/He and melanoma B16 in C57BL/6J.